Chen et al. demonstrated that the expression of CD73 (a cell-surface enzyme involved in adenosine-mediated immunosuppression) on host cells suppressed the antitumor effect of anti-4-1BB. Combination of anti-CD73 and anti-4-1BB led to tumor regression in mice with TGFβ-low tumors via a preferential expansion of intratumoral IFNγ-secreting CD73-CD8+ T cells and a decrease in Tregs. However, this treatment was ineffective in TGFβ-high tumors, as TGFβ maintained CD73 expression on T cells. Similar results were observed with anti-GITR or anti-OX40 treatments.
Agonist antibodies (Ab) directed against costimulatory molecules on the surface of antigen-primed T cells are in various stages of pre-clinical and clinical trials, albeit with limited therapeutic benefit as single agents. The underlying mechanisms of action remain incompletely understood. Here, we demonstrate an inhibitory role of ecto-enzyme CD73 for agonistic anti-4-1BB/CD137 Ab therapy. In particular, anti-4-1BB treatment preferentially drives CD73(-) effector T cell response for tumor inhibition. Anti-CD73 neutralizing Ab further improves anti-4-1BB therapy associated with enhanced anti-tumor T cell immunity. However, the TGF-beta-rich tumor milieu confers resistance to anti-4-1BB therapy by sustaining CD73 expression primarily on infiltrating CD8(+) T cells across several tumor models. TGF-beta blockade results in downregulation of CD73 expression on infiltrating T cells and sensitizes resistant tumors to agonistic anti-4-1BB therapy. Thus, our findings identify a mechanism of action for more effective clinical targeting of 4-1BB or likely other costimulatory molecules.
Author Info: (1) Department of Medicine-Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, US
Author Info: (1) Department of Medicine-Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA. Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan, China. (2) Department of Medicine-Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA. (3) Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan, China. (4) Department of Medicine-Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA. (5) Department of Medicine-Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA. (6) Department of Medicine-Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA. (7) Department of Medicine-Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA. Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China. (8) Department of Medicine-Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA. Department of Allergy Center, Otorhinolaryngology Hospital, The First Affiliated Hospital of Sun Yat-sen University, 510080, Guangzhou, China. (9) Department of Otolaryngology-Head and Neck Surgery, Affiliated Eye, Ear, Nose and Throat Hospital, Fudan University, 200031, Shanghai, China. (10) Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan, China. (11) Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA. (12) Department of Medicine-Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA. (13) Department of Medicine-Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA. bin.zhang@northwestern.edu. Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan, China. bin.zhang@northwestern.edu.
